rs190215588

Variant names:

• chr3-69879358-C-T
• rs190215588
• NM_001354604.2:c.329C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-69879358-C-T
• chr3-69879358-C-A
• chr3-69879358-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_001354604.2(MITF):​c.329C>T​(p.Thr110Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T110T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.54
• Publications: 7 publications found

Genes affected

MITF (HGNC:7105): (melanocyte inducing transcription factor) The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

MITF Gene-Disease associations (from GenCC):

• Tietz syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• Waardenburg syndrome type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Waardenburg syndrome type 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• melanoma, cutaneous malignant, susceptibility to, 8

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Waardenburg syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Waardenburg-Shah syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1092709).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000184 (28/152330) while in subpopulation AMR AF = 0.000327 (5/15306). AF 95% confidence interval is 0.000182. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354604.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	NM_001354604.2	MANE Select	c.329C>T	p.Thr110Met	missense	Exon 2 of 10	NP_001341533.1	O75030-1
	MITF	NM_001354605.2		c.326C>T	p.Thr109Met	missense	Exon 2 of 10	NP_001341534.1
	MITF	NM_198159.3		c.329C>T	p.Thr110Met	missense	Exon 2 of 10	NP_937802.1	O75030-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.329C>T	p.Thr110Met	missense	Exon 2 of 10	ENSP00000295600.8	O75030-1
	MITF	ENST00000956046.1		c.329C>T	p.Thr110Met	missense	Exon 2 of 11	ENSP00000626105.1
	MITF	ENST00000956043.1		c.329C>T	p.Thr110Met	missense	Exon 2 of 11	ENSP00000626102.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000165 AC: 41 AN: 248876 AF XY: 0.000178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.000158 AC XY: 115 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1112002

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74494

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68034

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	not specified (2)
-	1	-	MITF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.096
Sift	Benign	0.12	T
Sift4G	Benign	0.071	T
Polyphen		0.54	P
Vest4		0.47
MVP		0.25
MPC		0.32
ClinPred		0.091	T
GERP RS		6.0
Varity_R		0.055
gMVP		0.62
Mutation Taster		=66/34	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs190215588; hg19: chr3-69928509; COSMIC: COSV58882407; COSMIC: COSV58882407;